Abstract The recent Zika virus (ZIKV) outbreaks present to the world a new health challenge. Although ZIKV infection is linked to neurological disorders, especially in fetus and newborns, little is known about ZIKV and host interactions. Nonetheless, it has been shown that immature neuronal cells are highly susceptible to ZIKV infection and undergo ZIKV-induced cell death. We have independently developed a CRISPR-Cas9-based genome wide knockout screening method, and improved the design of sgRNA. In this proposal, we will take advantage of our technical expertise to perform genome wide screening of host factors in immature neuronal cells that promote ZIKV-induced cell death. Conversely, we will use the nuclease deficient CRISPR- dCas9 to perform genome wide activation screening to identify host restriction factors that protect the immature neuronal cells from ZIKV-induced cell death. We will validate the identified host factors by independent methods and functional assays. Our studies will help better understand ZIKV host interactions and provide potential targets for therapeutic intervention of ZIKV-mediated neurological disorders.